Abstract In a free-running Y-maze exploratory task mice tend to enter the least recently visited compartment (spontaneous alternation). Treatment with d- or l-amphetamine produced a dose-dependent increase in locomotor activity and resulted in animals successively exploring two compartments of the Y-maze only (perseveration). Whereas five daily injections of d-amphetamine (10 mg/kg) or /-amphetamine (45 mg/kg) did not result in tolerance to the locomotor-stimulating properties of the drug, a dose-dependent attenuation of the perseverative tendency was observed. Moreover, symmetrical cross-tolerance between the isomers was apparent. Since formation of p-hydroxynorephedrine is stereo-specific to the d-isomer, these data suggest that this possible false transmitter does not play a primary role in the development of the tolerance. Alternative explanations which may account for the behaviour-specific tolerance were considered.